Nevi are among the most common skin lesions in man and are critically important risk markers and potential precursors of malignant melanoma. Observations from the initial funding cycle of this project are changing our understanding of the natural history of nevi. We observed that nevus involution is common in childhood. We further observed two subsets of nevi with distinct dermoscopic patterns (globular versus reticular), that these distinct patterns remain stable in childhood, and that they have different size and anatomic distributions on the back. An additional highly novel observation in our study has been the recognition of subtle reticular and globular dermoscopic patterns in normal appearing skin that correlate with the pattern of the overlying nevi, and in the case of the globular skin pattern, correlate with the presence of previously unrecognized sub-clinical aggregates of nevus cells. Lastly, we observed that by the 5th grade a minority of children have developed nevi with a complex dermoscopic pattern. Here, we propose to build on these observations by using a longitudinal study design in an expanded sample from the same population-based cohort to test the following hypotheses: (1) Ongoing sun exposure impacts the evolution and involution of nevi in adolescence, (2) There are two dermoscopically recognizable subsets of nevi that are distinguishable based on their anatomic distribution and their differing associations with pigmentation phenotype, genotype, and presence of subclinical nevus aggregates; and (3) dermoscopically complex nevi in childhood are predictors of a high risk nevus phenotype in late adolescence. We will employ the cutting edge imaging technologies of 3- dimensional total body photography and in vivo reflectance confocal microscopy to accomplish these goals. The insights into nevus classification, etiology, and evolution gained from this study are anticipated to have significant public health, clinical, and scientific benefits. They will lead to better targeting of melanoma prevention in childhood and adolescence through improved risk stratification. These insights will also enhance studies of the biology of melanoma through the distinction of varied nevus associated pathways of melanocytic tumor progression. And, they will permit education of clinicians about the changes that routinely occur in nevi in adolescence which, in turn, should lead to a reduction of the large number of unnecessary nevus excisions in this age group. PUBLIC HEALTH RELEVANCE: Moles are potential precursors and important risk markers for malignant melanoma, the deadliest form of skin cancer. The proposed study - focused on children and adolescents - is designed to increase our understanding of different types of moles, how they evolve, and the factors that contribute to their development. The knowledge gained from this study is expected to help target melanoma prevention efforts in childhood and adolescence to those at greatest risk, to improve our understanding of how melanoma develops, and to reduce the large number of unnecessary excisions of moles that currently occur in adolescents.